Sixteen-year-old homeschooled Cady Heron (Lindsay Lohan) and her zoologist parents (Ana Gasteyer and Neil Flynn) return to the United States after a 12-year research trip in Africa, settling down in Evanston, Illinois. Attending a public school for the first time, Cady meets new classmates Janis Ian (Lizzy Caplan) and Damian Leigh (Daniel Franzese). The two educate Cady on the school's various cliques and warn her to avoid the most popular and infamous one, the "Plastics", who are led by queen bee Regina George (Rachel McAdams) and include rich but insecure Gretchen Wieners (Lacey Chabert) and sweet airhead Karen Smith (Amanda Seyfried). The Plastics take an interest in Cady, and invite her to sit with them at lunch. Seeing that Cady is getting along with the Plastics, Janis hatches a plan of revenge against Regina for some past slight, using Cady as the infiltrator.

Cady soon learns about Regina's "Burn Book", a journal filled with rumors, secrets, and gossip about the other girls and some teachers at school. Despite this discovery, Cady decides to forgo Janis's scheme for ethical reasons. Meanwhile, Cady begins to have a crush on Regina's ex-boyfriend, Aaron Samuels (Jonathan Bennett), whom a jealous Regina proceeds to steal back at a Halloween party in front of Cady. This spurs Cady to fully commit to Janis's plan to cut off Regina's "resources", which involve breaking Regina and Aaron up, tricking her into eating nutrition bars that actually make her gain weight, and turning Regina's fellow Plastics against her. In the process, Cady unwittingly remakes herself in Regina's image, becoming spiteful and superficial, and abandons Janis and Damian.

When Regina is finally made aware of Cady's treachery, she retaliates by spreading the contents of her Burn Book all over the school, quickly inciting a riot. To avoid suspicion, Regina inserts a fake libel of herself in the book in order to blame Cady, Gretchen, and Karen, the only female students not mentioned in the book. Karen convinces Principal Duvall (Tim Meadows), that they did not spread the Book. Duvall soon quells the riot, and gathers all the girls in the school in the gymnasium. Math teacher Ms. Norbury (Tina Fey), whom the Burn Book defamed as a drug dealer, makes the girls face the terrible way they all treat each other, confess their transgressions, and apologize to each other and the teachers. When Janis's turn comes, she confesses her plan to destroy Regina with Cady's help, and openly mocks Regina with the support of the entire school. Pursued by an apologetic Cady, Regina storms out and gets hit by a school bus, breaking her spine.

Without any friends, shunned by Aaron, and despised by the school, Cady takes full blame for the Burn Book and becomes an outcast. After making amends with Regina, Cady's guilt soon dissolves and she returns to her old personality. As part of her punishment for lying and failing Ms. Norbury's class, she joins the Mathletes in the state championship finals, and ends up winning the competition for her team after her opponent answers incorrectly. At the Spring Fling dance, Regina's new boyfriend, Shane Oman, is elected King, while Cady is elected Queen. Onstage, Cady declares that all her classmates are wonderful in their own way, breaks her plastic tiara, and distributes the pieces to some other girls. She then makes amends with Janis and Damian, reconciles with Aaron, and reaches a truce with the Plastics.

By the start of the new school year, the Plastics have disbanded. Regina has joined the lacrosse team to deal with her anger, Karen has become the school weather reporter (claiming earlier that her breasts can tell when it is raining), and Gretchen joins the "Cool Asians". Aaron graduates from high school and attends Northwestern University, Janis begins dating Kevin Gnapoor, whom she initially despised, and Cady declares that she is now normal. A group of new "Junior Plastics" has arisen, and Cady imagines them being hit by a bus.

Lindsay Lohan first read for Regina George, but the casting team felt she was closer to what they were looking for in the actress who played Cady, and since Lohan feared the "mean girl" role would harm her reputation, she agreed to play the lead. Rachel McAdams was cast as Regina because Fey felt McAdams being "kind and polite" made her perfect for such an evil-spirited character. Amanda Seyfried also read for Regina, and the producers instead suggested her for Karen due to Seyfried's "spacey and daffy sense of humor". Both Lacey Chabert and Daniel Franzese were the last actors tested for their roles. Lizzy Caplan was at first considered too pretty for the part of Janis, for which director Mark Waters felt a "Kelly Osbourne-like actress" was necessary, but Caplan was picked for being able to portray raw emotion. Fey wrote two roles based on fellow SNL alumni, Amy Poehler (whom Fey thought the producers would not accept for being too young) and Tim Meadows, and the cast ended up with a fourth veteran of the show, Ana Gasteyer.[9]

In its opening weekend, the film grossed $24.4 million in 2,839 theaters in the United States, ranking #1 at the box office and averaging $8,606 per venue.[2] By the end of its run, Mean Girls grossed approximately $86.1 million domestically and $43 million internationally, totaling $129 million worldwide.[2]

Mean Girls received generally positive reviews, critics lauded McAdams' performance and labeled it as Lohan's and Seyfried's breakthrough performances. Review aggregation website Rotten Tomatoes gives it a rating of 84%, based on 176 reviews, with the site's critical consensus stating that the film is "funnier and more smartly written than the average teen comedy."[11] On Metacritic, the film has a score of 66 out of 100, based on 39 critics, indicating "generally favorable reviews".[12]

Ann Hornaday of The Washington Post stated that it "Boasts a one-two-three punch in star Lindsay Lohan, screenwriter Tina Fey and director Mark Waters, and, indeed, it delivers a knockout". The screenplay was highly praised by critics with Peter Travers of Rolling Stone calling it "comic gold".[13] In November 2012, Rotten Tomatoes named it in its 'Top 50 Greatest Teen Comedies'.[14]

Mean Girls was released on VHS and DVD in North America on September 21, 2004, five months after it opened in theaters. It was released in a widescreen special collector's edition and a fullscreen collector's edition, both including several deleted scenes, a blooper reel, three interstitials, the theatrical trailer, previews, and three featurettes.[16] A Blu-ray version of the film was released on April 14, 2009.

Mariah Carey expressed several times that she is a fan of the film, using some quotes from the film in several interviews. Carey released a single, "Obsessed", which begins with an interlude quote where she says, "And I was like, 'Why are you so obsessed with me?'", a line said by Regina in the film. Carey's ex-husband, Nick Cannon revealed the song was inspired by the film itself.[22] She then referenced the film again in 2013 during an episode of American Idol.

In August 2013, the White House tweeted a quote from the film and made a reference to President Obama's dog, Bo.[23][24]Taco Bell tweeted a reply to the tweet, also using one of the quotes from the film.[25]

In an interview about the film, Fey noted, "Adults find it funny. They are the ones who are laughing. Young people watch it like a reality show. It's much too close to their real experiences so they are not exactly guffawing."[26]Entertainment Weekly put it on its end-of-the-decade, "best-of" list, saying, "'Fetch' may never happen, but 2004's eminently quotable movie is still one of the sharpest high school satires ever. Which is pretty grool, if you ask me!"[27] In 2006, Entertainment Weekly also named it the twelfth best high school film of all time, explaining: "There was a time when Lindsay Lohan was best known for her acting rather than her party-hopping. Showcasing Lindsay Lohan in arguably her best role to date, this Tina Fey-scripted film also boasts a breakout turn by Rachel McAdams as evil queen bee Regina George (Gretchen, stop trying to make 'fetch' happen! It's not going to happen!). While Mean Girls is technically a comedy, its depiction of girl-on-girl cattiness stings incredibly true."

At the 2013 People's Choice Awards, Jennifer Lawrence mentioned the film in her speech when she won "Favorite Movie Actress" [28]

October 3 has been dubbed on social media as "Mean Girls Day" in reference to a quote from the movie.[29]

The 6th episode of How to Get Away With Murder season 3 included several references to the film, including Aja Naomi King's character Michaela Pratt using the line "you can't sit with us"; Viola Davis character Annalise Keating eating her lunch in a toilet cubicle after feeling like an outcast; Karla Souza's character Laurel Castillo using sweat pants on a monday and Behzad Dabu's character Simon Drake calling several other students "mean girls".[30]

Adapted from another book penned by Rosalind Wiseman, Mean Moms would be written by Sean Anders and John Morris, and would star Jennifer Aniston as a mom facing the cut-throat life of modern suburbia. However, in May 2014, New Line Cinema pulled the film from its proposed release date of May 2015; even though the film is still slated for development, there is not currently a release date for the spin-off.[34] On October 7, it was announced that the film was added to the California Film Tax Credit program for the 2014–15 fiscal year, in which the production must start in California within 180 days of notification from the state to receive the $6.7 million production tax credit.[35] In May 2015, it was confirmed the project was still happening and Sean Anders would direct the film;[36] in late 2015 Anders told Cinema Blend the project was stalled.[37]

On January 28, 2013, Fey confirmed that a musical adaption of Mean Girls is in the works. Tina Fey will be the writer and possibly the director of the musical while 30 Rock composer and Fey's husband Jeff Richmond, will work on the music. Paramount will also be involved.[38] It will premiere at Washington DC in late 2017.[39]

In late September 2014, discussions arose that Lohan had pitched an idea to Fey for a sequel. In October 2014, Lohan, along with other cast members of the original film, asked Fey to write a screenplay for a sequel. The idea was brought up during a 10th anniversary for the film in People magazine.[40] No further development has been announced as of yet.